The invention relates to the new use of antagonists of the quisqualate receptor complex or its physiologically compatible salts as pharmaceutical agents for the prevention and treatment of Parkinson's disease, as well as pharmaceutical agents which contain these compounds and their combination with anti-Parkinson's agents with synergistic action.
In the central nervous system of mammals, including humans, high concentrations of excitatory amino acids, such as glutamate and aspartate, are present (Fonnum, F., J. Neurochem. 42: 1-11, 1984). For the excitatory amino acids, various receptors exist, which are identified according to their specific agonists as N-methyl-D-aspartate (NMDA) receptor, kainate (KA) receptor and quisqualate (QUIS) receptor. The quisqualate receptors are also named AMPA receptors according to the specific agonists (RS)-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. The synaptic function of the excitatory amino acid L-glutamate is mainly imparted by AMPA receptors.
From clinical and animal-experimental findings, there are indications that in the case of Parkinson's disease (PD), increased glutamatergic neurotransmission in various nuclei of the basal ganglia results as a result of the striatal deficiency of dopamine. The neostriatum (NEO) represents the input structure of the basal ganglia: it obtains a massive glutamatergic projection from the cortex and the dopaminergic nigrostriatal pathway, which degenerates in the case of PD, from the substantia nigra pars compacta (SNC). From the NEO, there are direct pathways to the output nuclei of the basal ganglia, the internal pallidum link (GPi) and the substantia nigra pars reticulata (SNR), as well as indirect pathways, which run through the outer pallidum link (GPe) and the subthalamic nucleus (STH). The STH receives a direct glutamatergic innervation of its own from the cortex; its neurons projecting to the output nuclei also use L-glutamate as a transmitter.
The synaptic functions of dopamine in the NEO are complex. Its effect on the striatal neurons projecting to the GPe is mainly inhibitory, so that as a result of the striatal dopamine deficiency, as it is present in the case of PD, the excitatory glutamatergic influences on these neurons predominate. Since both the striatal pathway to the GPe, and the pathway projecting to the STH starting from there are inhibitory, in the case of PD in the STH the phenomenon of the disinhibition results with the increase of the tonic cellular activity. By its glutamatergic projections, the STH finally produces a pathologically increased neuronal activity in the output nuclei of the basal ganglia. Tests on animal models of the PD show that after administration of dopaminergic substances, a normalization of the increased excitatory neurotransmission results, which runs parallel to the "clinical" improvement.